Process for the preparation of α-acyloxy β-formamido amides

ABSTRACT

The present invention relates to a process for the preparation of a compound of the general Formula (I), comprising: a) reacting a compound of the general Formula (II) with a compound of the Formula III R 2 COOH and a compound of the general Formula IV R 3 NC under such conditions that compound I is formed, wherein R 1  represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R 2  represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R 3  represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl structure. In further aspect the subject invention relates to the use of the obtained products as intermediates for various peptidomimetics, and preferably as a building block in a convergent synthesis of prolyl dipeptide structures.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application of PCT Application No.PCT/EP2010/063657, filed on Sep. 16, 2010, which claims the benefit andpriority to U.S. Patent Application No. 61/307,873, filed Feb. 25, 2010.The entire disclosures of the applications identified in this paragraphare incorporated herein by references.

FIELD OF THE INVENTION

The present invention relates to α-acyloxy β-formamido amides, methodsfor their preparation, and their use as intermediate for the preparationof isocyanide building block for the preparation of prolyl peptideinhibitors of disease-associated targets.

BACKGROUND OF THE INVENTION

α-hydroxy-β-aminocarboxylic acid and amide derivatives are found in avariety of natural products and pharmaceutically active substances.

Subunits incorporating the α-hydroxy-β-aminocarboxylic acid motif havebeen termed “norstatine” derivatives, and serve as key intermediates forthe synthesis of the general class of P1-α-ketocarboxylictransition-state inhibitors of serine or cysteine proteases. Suchinhibitors are finding increasing applications in medicine for thetreatment of a diverse array of disease states including thrombosis,cancer, and osteoporosis.

Towards this end, α-hydroxy-β-aminocarboxylic acid, ester and amidederivatives serve an important role as the most common precursors forthe preparation of these α-hydroxy-β-aminocarboxylic acid-incorporatingdrug candidates.

Electrophilic α-dicarbonyl compounds are regarded as interesting andhighly reactive functional arrays which are capable of undergoing amyriad of transformations.

Such chemical properties can be exploited in novel and therapeuticallyuseful ways by strategically incorporating these reactiveα-ketocarboxylic moieties into a peptidic or peptidomimetic matrix.

Multicomponent reactions (MCRs) such as the Passerini and Ugi reactionsoffer the ability to rapidly and efficiently generate collections ofstructurally and functionally diverse organic compounds. The Passerinireaction is a chemical reaction involving isocyanides, aldehydes orketones, and carboxylic acids to form α-acyloxy amides. Compounds thatare available through the Passerini reaction may form highly valuablebuilding blocks in the convergent synthesis of compounds with medicinaleffects, such as for instance the prolyl dipeptide inhibitors Telapreviror Boceprevir.

WO2007/0022450 discloses for instance the preparation of acyclopropylamide by the coupling of Cb-norvalinal with cyclopropylisocyanide in the presence of trifluoroacetic acid. The obtainedcompound is then deprotected, and the aminoalcohol then employed in asynthesis of Telaprevir. However, the disclosed synthesis is cumbersome,and only allows for a limited yield and variation of the building blocksinvolved.

Accordingly, the access to such compound through a more selective andhigher yielding route would be highly desirable.

SUMMARY OF THE INVENTION

The subject invention now provides for a synthesis ofα-hydroxy-aminocarboxylic acid derivatives such as to α-acyloxyβ-formamido amides that advantageously can be employed in multicomponentreactions (MCRs), such as Passerini and Ugi reactions, which allowconvergent syntheses with high atom and step efficiency in good yield.

Accordingly, the present invention relates to a process for thepreparation of a compound of the general formula I

comprising:a) reacting a compound of the general formula II:

with a compound of the formula III:R²—COOH  (III),and a compound of the general formula IVR³—NC  (IV)wherein R¹ represents a hydrogen atom, a substituted or unsubstitutedalkyl, alkenyl, alkynyl, aromatic or non-aromatic, monocyclic,polycyclic or alkylcycloalkyl or a heterocyclic structure;R² represents a substituted or unsubstituted alkyl, alkenyl, alkynyl,aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclicstructure; andR³ represents a substituted or unsubstituted alkyl, alkenyl, or alkynylstructure, or a protective group that can reversible be removed.

In a first aspect, the present invention provides novel methods for thesynthesis of α-hydroxy-β-amino acid and amide derivatives according toformula I and intermediates thereto. These derivatives may beadvantageously be employed as intermediates for synthesis of peptidylα-ketoamides and α-hydroxy-β-amino carboxylic acid derivatives which areuseful as inhibitors of certain proteases, including serine and cysteineproteases.

The process preferably involves reacting an N-terminally protected aminoaldehyde with an isonitrile and a carboxylic acid to give an aminoα-acyloxy carboxamide. The acyl group may then be removed to give thederivative, or may advantageously remain in position. Alternatively, theprotecting group may removed and an acyl shift may advantageously takeplace. The reaction is performed under such conditions that compound Iis formed.

The process according to present invention provides an improvedsynthetic route to intermediates for the end target compounds, witheconomy of synthesis, namely fewer synthetic steps, improved yields,less consumption of reagents and fewer side products than are obtainedfollowing conventional synthetic routes.

In the process according to the invention, R¹ preferably represents ahydrogen, a straight chain alkyl, a branched chain alkyl, a cycloalkyl,an alkylene-cycloalkyl preferably —CH₂-cyclopropyl or —CH₂-cyclobutyl,an aryl, alkylene-aryl, SO₂-alkyl, SO₂-aryl, alkylene-SO₂-aryl,-alkylene-SO₂-alkyl, heterocyclyl or alkylene-heterocyclyl; CH₂CO—X—H,—CH₂CO—X-straight chain alkyl, —CH₂CO—X-branched chain alkyl,—CH₂CO—X-cycloalkyl, —CH₂CO—X-alkylene-cycloalkyl, —CH₂CO—X-aryl,—CH₂CO—X-alkylene-aryl, —CH₂CO—X-heterocyclyl,—CH₂CO—X-alkylene-heterocyclyl or —CH₂CO-aryl; wherein X represents O, Sor NH.

R² preferably represents hydrogen, a straight chain alkyl, a branchedchain alkyl, a cycloalkyl, an alkylene-cycloalkyl, an aryl, and/oralkylene-aryl.

R³ preferably represents a straight chain alkyl, a branched chain alkyl,a cycloalkyl, an alkylene-cycloalkyl, an aryl, and/or alkylene-aryl.

In a preferred embodiment of the subject invention, R¹ represents analkyl group such as ethyl or preferably n-propyl, or an alkylcycloalkylgroup, such as cyclobutylmethyl. More preferably R² preferably is alower carboxylic acid group, preferably an acetate group, and R³preferably is a cyclopropyl group.

The process according to the present invention further advantageouslycomprises a step b) of isolating the obtained compound I from thereaction mixture.

This may be done by any suitable method known to a skilled person, suchas extraction, chromatographic separation, distillation, crystallizationor otherwise suitable process or combinations thereof.

Alternatively, the compound remains in the reaction mixture, and theisocyanide compound is added to the mixture.

Preferably, the aldehyde compound according to formula II is derivedfrom a substituted 2-amino-1-ethanol according to general formula V:

Preferably, the alcohol is enantiomerically substantially pure, sincethis allows accessing a large number of different stereoisomericcompounds from substituted alcohols, thus from relatively simplebuilding blocks.

Compound II may advantageously be prepared from an substituted2-amino-1-ethanol according to general formula V by A) N-formylation,and B) by a selective oxidation of the primary alcohol of the obtainedN-formylated amino alcohol intermediate to an aldehyde.

Steps (A) and (B) may be performed by any suitable method known to aperson skilled in the art.

Preferably, step (B) includes a Dess-Martin oxidation of the alcohol toan aldehyde.

The oxidation is advantageously performed by employing a Dess-Martinoxidation. In this way, the stereogenic centre and various substituentsR¹ can be introduced from often commercially or synthetically readilyavailable 2-aminoethanols. A so-called Dess-Martin oxidation employs theDess-Martin Periodinane (DMP), a hypervalent iodine compound for theselective and very mild oxidation of alcohols to aldehydes or ketones,as disclosed for instance in Y. Yip, F. Victor, J. Lamar, R. Johnson, Q.M. Wang, J. I. Glass, N. Yumibe, M. Wakulchik, J. Munroe, S.-H Chen,Bioorg. Med. Chem. Lett. 2004, 14, 5007-5011.

The oxidation preferably may be performed in dichloromethane, chloroformof THF at room temperature, and is usually complete within 0.5-2 hours.Products are easily separated from the iodine-containing by-productsafter basic work-up.

Preferably, the Dess-Martin oxidation according to the invention isperformed in the presence of compound IV, in such a way that thealdehyde II that is formed during the Dess-Martin oxidation immediatelyreacts in a Passerini reaction with the acetic acid that is formed as aby-product of the Dess-Martin oxidation as carboxylic acid III andisocyanide IV. This has the tremendous benefit that the atomicefficiency of the reaction is increased, since the Dess-MartinPeriodinane (DMP) also provides a reactant for the second stage of thereaction, i.e., the Passerini three-component reaction. In addition, thecombination of two reaction steps in one pot is advantageous in terms ofboth time and resources, since among other benefits less solvent andmanpower are required due to the single workup stage, and since lessseparation steps by chromatography are required. Accordingly, compoundII is advantageously not isolated after step B), but the isocyanidecomponent IV is added to the reaction mixture after the oxidation iscomplete. In this case, the lower carboxylic acid, preferably aceticacid released from the Dess-Martin Periodinane acts as component III,thereby resulting in a carbon efficient process with minimal handlingand isolation issues. Moreover, the aldehyde compounds obtained candirectly be converted with high selectivity to compound (I) as definedherein above, which is usually more stable than the aldehyde component,thereby increasing the overall yield. Accordingly the present inventionalso relates to a process including combining the Dess-Martin oxidationin one pot with the Passerini reaction to afford α-acyloxy-β-formamidoamides (I) directly.

The process according to the present invention further advantageouslycomprises a step c) of subjecting compound Ito dehydrating conditions toobtain an isocyanide compound according to general formula VI:

-   -   wherein R¹, R² and R³ are as defined herein above.

This may advantageously be achieved for instance by treatment of theformamido compound (I) with phosgene, diphosgene(trichloromethylchlorofolurate), triphosgene [bis(trichloromethyl)carbonate], and/or POCl₃. The reaction step (c) usually performed in thepresence of a base, typically a tertiary amine base such astriethylamine or N-methylmorpholine.

Preferably, therefore, R² is a lower carboxylic acid, more preferablyacetate.

In a preferred embodiment of the subject process, R¹ is preferably is analkyl group, such as n-propyl, or an alkylcycloalkyl group, preferably—CH₂-cyclopropyl or —CH₂-cyclobutyl.

In a further preferred embodiment of the subject process, R³ is acycloalkyl or hydrogen, or a protective group as usually employed toreversibly protect primary amines.

In yet a further preferred embodiment of the subject process, R¹, R² andR³ are chosen such that the compound according to formula VI has astructure according to general formula VII:

In yet a further preferred embodiment of the subject process, R¹, R² andR³ are chosen such that the compound according to formula VI has astructure according to general formula VIII:

wherein R¹ represents a lower carboxylic acid group, preferably acetate,and R² represents reversibly attached protective group.

The isocyanide compound VI can advantageously be employed in reactionprocesses such as Ugi or related multicomponent reactions that make useof isocyanide compounds in the convergent synthesis of complexstructures, such a prolyl dipeptide structures.

Accordingly, the subject process further advantageously comprisesreacting the compound according to formula IV with a compound having thegeneral formula IX:

or the respective diastereomers, anda compound of the general formula X:R⁷—COOH  (X),to obtain a compound according to general formula XI or its respectivediastereomers

wherein R⁴ represents each independently, or jointly a substituted orunsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-,di- or tricyclic, or heterocyclic structure, andR⁵ represents each independently a hydrogen atom, a substituted orunsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-,di- or tricyclic, or heterocyclic structure,R⁶ represents the structure derived from compound I wherein R¹, R² andR³ are defined herein above, andR⁷ represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl,or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- ortricyclic, or heterocyclic structure, and R⁷ represents a substituted orunsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromaticaromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclicstructure, under conditions that compound XI is formed.

In the case of R⁵ being different from hydrogen, the diastereomers ofcompound IX referred to above include the following compounds of generalformula IXa and IXb, respectively:

resulting predominantly in the compounds of general formula XIa and XIb,respectively:

The (3R,7S)-diastereomers, i.e. the diastereomers having the oppositeconfiguration of the substituents R⁴ can also be employed, yielding theequivalent (3R,7S)-configured proline derivatives XI.

Preferably, both substituents R⁵ represent hydrogen, and bothsubstituents R⁴ jointly form a substituted or unsubstituted 3-, 4-, 5-,6-, 7- or 8 membered ring structure. More preferably, R⁴ is chosen suchthat the compound according to formula I has the structure according toformula XII:

according to formula XIII:

or according to formula XIV:

Preferably, R⁷ represents a structure according to general formula XV:

wherein R^(a) and R^(b) each independently represents a hydrogen atom, ahalogen atom, a lower alkyl group comprising from 1 to 4 carbon atoms, alower alkyl group substituted by halogen, a cycloalkyl group, an arylgroup, a lower alkoxy group, a lower thioalkyl group, a cycloalkyloxygroup, an aralkyloxy group or an alkanoyl group; a hydroxyl group, anitro group, a formyl group, an amino group which may be protected orsubstituted, a cycloalkyloxy, aralkyloxy, alkanoyl, ureido or mono-, di-or tricyclic heterocyclic group, all of which groups may optionally besubstituted.

In a preferred embodiment of the subject process, the compound accordingto formula XII

is reacted with a compound according to general formula XVI:

and a compound according to general formula VII as defined herein aboveto obtain a compound according to formula XVII:

After the reaction, compound XVII may advantageously be isolated fromthe reaction mixture.

The subject process further preferably comprises subjecting the compoundaccording to formula XVII to a saponification reaction to remove theacetate from the secondary alcohol at the α-hydroxy-β-amino acidstructure.

The saponification preferably is carried out by contacting the compoundaccording to formula XVII with an alkaline metal carbonate, preferablyK₂CO₃ in a suitable solvent, to obtain a saponified alcohol productaccording to formula XVII a (not depicted here). The subject inventionalso relates to compounds XVII and XVIIa.

The released intermediate compound XVIIa comprising the secondaryalcohol is then subjected to a selective oxidation to a ketone to formcompound XVIII,

This compound, which is also known as Telaprevir, could be prepared inhigher yields than any previously disclosed processes according to theprocess of the present invention.

In a further preferred embodiment of the subject process, a compoundaccording to general formula XVIII above is reacted with an acidcompound according to general formula XIX:

and an isocyanate compound according to the present invention accordingto general formula XXI:

This reaction will result in compound XXI,

which may advantageously be saponified to a secondary alcohol andsubsequently oxidized to a ketone, thereby yielding, after removal undersuitable conditions of the R² group, a compound according to formulaXXIII:

also known as Boceprevir.

The process according to the present invention advantageously permits toselectively produce the two diastereomers according to the generalformula XXIIa:

and according to the general formula XXIIb, respectively,

The subject invention therefore also relates to a process wherein XIIaor XIIb are selectively prepared, and to the thus obtained compoundsXXIa or XXIb as well as to compounds XIIa or XIIb.

Suitable solvents for the subject reaction are polar protic and aproticorganic solvents, including methanol, ethanol, 2-propanol and otheralcohol solvent, tetrahydrofuran, 1,4-dioxane, acetonitrile, and/ormixtures of these solvents with water or less polar organic solvents,such as dichloromethane or chloroform.

The saponification or removal of the ester group through hydrolysis maybe performed by any suitable method known to a skilled person.Preferably, it is carried out by contacting the obtained reactionproduct according to formula I with an alkaline metal carbonate, morepreferably K₂CO₃ in a suitable solvent, to obtain a saponified alcoholproduct. The saponified alcohol product may then advantageously beoxidised selectively at the secondary alcohol function, preferablywithout affecting the other structures on the compound, to yield aketone compound.

The selective oxidation is preferably carried out by contacting thesaponified alcohol product with a suitable oxidant in a suitablesolvent. Suitable solvents include dichloromethane, THF, ethyl acetate,DMSO. Suitable oxidants include hypervalent iodine reagents such as IBX,Dess-Martin periodinane, etc., or a combination of TEMPO and PhI(OAc)₂or related reagents.

The present invention further advantageously also relates to all novelintermediates obtainable by the subject process, more preferably tocompounds XIV and XIX prior to saponification, to the compounds havingthe saponified secondary alcohols, and to all novel intermediates andbuilding blocks.

EXPERIMENTAL PART Example 1 Synthesis of (S)-2-Formamidopentanal (1)

Compound (I) and its Dimeric Form

Dess-Martin periodinane (5.514 g, 13 mmol) was added to a solution of(S)-2-formamido-1-pentanol (1.31 g, 10 mmol) in CH₂Cl₂ (100 ml) at roomtemperature. The white suspension was stirred for 2 days andsubsequently 35 ml MeOH was added and stirred for 30 minutes. Theresulting suspension was filtrated and the filtrate was concentrated invacuo. The crude product was purified by silica gel flash chromatography(cHex:EtOAc=1:4) to give compound I (1.08 g, 8.29 mmol, 83%) as a whitesolid. NMR analysis indicates that compound I is in equilibrium with itscyclic dimmer, which was found to form a mixture of diastereomers.

[α]_(D) ²⁰=+37.6 (c=0.745, CHCl₃); ¹H NMR assigned to the monomer(250.13 MHz, CDCl₃): δ=8.22 (s, 1H), 7.84 (s, 1H), 7.10 (m, 1H), 5.31(m, 1H), 1.52 (m, 4H), 0.95 (m, 3H); ¹³C NMR assigned to the monomer(100.61 MHz, CDCl₃): 198.8 (CH), 161.7 (CH), 57.4 (CH), 30.8 (CH₂), 18.4(CH₂), 13.7 (CH₃); ¹H NMR assigned to the dimer (400.13 MHz, CDCl₃) 8.22(s, 2H), 5.26 (m, 2H), 3.72 (m, 2H) 1.52 (m, 8H), 0.95 (m, 6H ¹³C NMR(100.61 MHz, CDCl₃) assigned to the dimer: 161.7 (CH), 89.8 (CH), 63.1(CH), 30.8 (CH2), 18.4 (CH2), 13.7 (CH3); IR (neat): ν_(max) (cm⁻¹):3325 (s), 2959 (s), 1649 (s), 1530 (s), 1381 (m), 1123 (w); HRMS (ESI,4500 V): m/z calc. for C₆H₁₂NO₂ ⁺ ([M+H]⁺) 130.0863. found 130.0858.

Example 2 Synthesis from Compound I as Obtained in Example 1

(3S)-2-acetoxy-N-cyclopropyl-3-formamidohexanoyl amide (3)

Aldehyde compound I (0.892 g, 6.91 mmol) was added to a solution ofcyclopropyl isocyanide (0.410 g, 6.12 mmol) in CH₂Cl₂ (110 ml) andstirred for 5 minutes at room temperature. Acetic acid (0.711 ml, 0.747g, 12.44 mmol) was added and the yellow reaction mixture was stirred for3 days at room temperature. The reaction mixture was washed twice with100 ml saturated Na₂CO₃, followed by drying with Na₂SO₄ andconcentration in vacuo. The crude was purified by silica gel flashchromatography (5% MeOH in CH₂Cl₂, 1% triethylamine).(3S)-2-acetoxy-N-cyclopropyl-3-formamidohexanoyl amide (0.99 g, 3.87mmol, 56%) was obtained as a white solid as a 78:22 mixture ofdiastereomers.

Example 3 In situ-preparation of(3S)-2-acetoxy-N-cyclopropyl-3-formamidohexanoyl amide (3) withoutisolation of the compound obtained in example 1

Dess-Martin periodinane (5.66 g, 12.3 mmol) was added to a solution of(S)—N-(1 hydroxypentan-2-yl)formamide (1.15 g, 8.8 mmol) in CH₂Cl₂ (12ml) at room temperature. The white suspension was stirred for 60 minutesand subsequently cyclopropyl isocyanide (0.74 g, 10.0 mmol) was addedand stirred for 48 hours. The resulting suspension was filtrated andwashed twice with 10 ml saturated Na₂CO₃, followed by drying with Na₂SO₄and concentration in vacuo. The crude product was purified by silica gelflash chromatography (5% MeOH in CH₂Cl₂, 1% triethylamine) to givecompound 3 (1.34 g, 5.22 mmol, 60%) as a pale yellow solid as a 78:22mixture of diastereomers.

¹H NMR (130° C., 400.13 MHz, DMSO-d₆): δ=8.03 (s, 1H), 7.52 (m, 1H),7.30 (m, 1H), 4.89 (d, J=4.4, 1H), 4.28 (m, 1H), 2.65 (m, 1H), 2.17 (s,3H), 1.27-1.47 (m, 4H), 0.89 (t, J=7.2, 3H), 0.63 (m, 2H), 0.48 (m, 2H);¹³C NMR (125.78 MHz, DMSO-d₆): δ=169.8 (C), 168.5 (C), 160.6 (CH), 74.4(CH), 47.5 (CH), 22.2 (CH), 18.4 (CH₃), 13.6 (CH₃), 5.7 (CH₂); IR(neat): ν_(max) (cm⁻¹) 3283 (s), 2961 (w), 1744 (m), 1661 (s), 1530 (s),1238 (s); HRMS (ESI, 4500 V): m/z calcd. for C₁₂H₂₀N₂O₄Na⁺ ([M+Na]⁺)279.1315. found 279.1325.

Example 4 Preparation of(3S)-2-acetoxy-N-cyclopropyl-3-isocyano-hexanoyl amide (4)

(3S)-2-acetoxy-N-cyclopropyl-3-isocyano-hexanoyl amide (4)

N-methylmorpholine (0.57 ml, 0.562 g, 5.56 mmol) was added to a solutionof (S)-1-(cyclopropylamino)-3-formamido-1-oxohexan-2-yl acetate (0.713g, 2.78 mmol) in CH₂Cl₂ (40 ml) at room temperature. The reactionmixture was cooled to −78° C. and triphosgene (0.289 g, 0.97 mmol) wasquickly added and stirred for 5 minutes at this temperature. Theresulting yellow solution was wanted up to −30° C. and was stirred foranother 3 h. Subsequently, the reaction was quenched with water andextracted twice with CH₂Cl₂ (40 ml). The organic layers were collected,dried with Na₂SO₄ and concentrated in vacuo. The crude product waspurified by silica gel flash chromatography (2% MeOH in CH₂Cl₂) to give4 (0.578 g, 2.42 mmol, 87%) as a white solid.

¹H NMR (250.13 MHz, CDCl₃): δ=6.28 (s, 1H), 5.25 (d, J=2.5 Hz, 1H), 4.2(m, 1H), 2.74 (m, 1H), 2.24 (s, 3H), 1.55 (m, 4H), 0.96 (m, 3H), 0.84(m, 2H), 0.60 (m, 2H); ¹³C NMR (62.90 MHz, CDCl₃): δ=169.7 (C), 168.3(C), 74.4 (CH), 47.5 (CH), 22.0 (CH), 20.6 (CH₃), 18.5 (CH₂), 13.5(CH₃), 5.5 (CH₂); IR (neat): ν_(max) (cm⁻¹): 3267 (s), 2959 (m), 1745(m), 1643 (s), 1512 (m), 1221 (s); HRMS (ESI, 4500 V): m/z calcd. forC₁₂H₁₈N₂O₃Na⁺ ([M+Na]⁺) 261.1210. found 261.1214.

Example 5

General Structure of the Compound Obtained in Example 5

The Isocyanide obtained in Example 4 (0.549 g, 2.3 mmol) was dropwiseadded to a solution of (3S,&R) 3-azabicyclo-[3,3,0]oct-2-ene imine(0.252 g, 2.3 mmol) and(S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoicacid (0.602 g, 1.60 mmol) in CH₂Cl₂ (5 ml) at room temperature. Thisyellow solution was stirred for 72 hours and afterwards diluted with 5ml CH₂Cl₂. The reaction mixture was washed twice with saturated Na₂CO₃solution (10 ml) and twice with saturated NH₄Cl. The organic layers werecollected, dried with MgSO₄ and concentrated in vacuo. The crude productwas purified by silica gel flash chromatography (5% MeOH in CH₂Cl₂) togive 5 (0.876 g, 1.21 mmol, 76%) as a mixture of diastereomers.

¹H NMR (500.23 MHz, CDCl₃): δ=9.50 (s, 1H), 8.75 (d, J=2.5, 1H), 8.59(s, 1H), 8.35 (d, J=9.0, 1H), 6.84 (d, J=9.0, 1H), 6.44 (s, 1H), 5.20(d, J=3.0, 1H), 4.74 (d, J=9.5, 1H), 4.58 (t, J=7.5, 1H), 4.38 (m, 1H),3.37 (d, J=6.0, 1H), 2.82 (m, 1H), 2.69 (m, 1H), 2.11 (s, 3H), 1.26 (s,2H), 0.97 (s, 9H), 0.86 (m, 3H), 0.84-2.00 (m, 21H), 0.76 (m, 2H), 0.51(m, 2H); ¹³C NMR (125.78 MHz, CDCl₃): δ=170.5 (C), 169.3 (C), 162.9 (C),147.4 (CH), 144.6 (CH), 144.2 (C), 142.8 (CH), 74.4 (CH), 66.6 (CH),58.3 (CH), 56.6 (CH), 54.5 (CH₂), 44.9 (CH), 43.0 (CH), 41.3 (CH), 35.5(C), 26.4 (CH₃), 20.8 (CH₃), 19.1 (CH₂), 13.8 (CH₃), 6.6 (CH₂); ν_(max)(cm⁻¹): 3306 (m), 2928 (m), 2931 (m), 1743 (w), 1655 (s), 1520 (m), 1219(m); HRMS (ESI, 4500 V): m/z calcd. for C₃₈H₅₇N₇O₇Na⁺ ([M+Na]) 746.4212.found 746.4107.

Example 6

Telaprevir (Example 6)

250 μl of saturated K₂CO₃ was added to a solution of the compoundobtained in Example 5 (0.514 g, 0.75 mmol) in MeOH (20 ml) at roomtemperature. The reaction mixture was stirred for 30 minutes at roomtemperature resulting in a pale yellow suspension. After full conversion(as judged by TLC analysis), the reaction mixture was washed with 20 mlbrine, the aqueous layer was washed again with 10 ml CH₂Cl₂ (2×). Theorganic layers were collected, dried with MgSO₄ and concentrated invacuo, to yield a pale yellow solid. The yellow solid was dissolved inCH₂Cl₂ (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) wasadded at room temperature. The reaction mixture was stirred overnightbefore adding saturated NaHCO₃ solution (10 ml) and saturated Na₂S₂O₃solution (10 ml). This mixture was stirred for 10 minutes, separated andthe aqueous layers were washed with EtOAc (2×10 ml). The organic layerswere collected, dried with MgSO₄ and concentrated in vacuo to give thecrude product as an 83:13:4 mixture of diastereomers. After silica gelflash chromatography (1% MeOH in CH₂Cl₂), 5 (0.412 mg, 0.61 mmol, 80%)was obtained as a white solid. ¹H NMR (500.23 MHz, DMSO-d₆): δ=9.19 (d,J=1.4 Hz, 1H), 8.91 (d, J=24.5 Hz, 1H), 8.76 (dd, J=1.5, 2.5 Hz, 1H),8.71 (d, J=5.3 Hz, 1H), 8.49 (d, J=9.2 Hz, 1H), 8.25 (d, J=6.8 Hz, 1H),8.21 (d, J=8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J=6.5, 9.0 Hz, 1H), 4.53(d, J=9.0 Hz, 1H), 4.27 (d, J=3.5 Hz, 1H), 3.74 (dd, J=8.0, 10 Hz, 1H),2.74 (m, 1H), 3.64 (d, J=3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H),0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); ¹³C NMR (125.78 MHz,CDCl₃): δ=197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9(C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH),53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1(CH), 28.0 (CH), 26.4 (CH₃); ν_(max) (cm⁻¹): 3302 (m), 2928 (m), 2858(w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); HRMS (ESI, 4500 V): m/zcalcd. for C₃₆H₅₃N₇O₆Na⁺ ([M+Na]⁺) 702.3950. found 702.3941.

The invention claimed is:
 1. A process for preparing a compound offormula I:

comprising: a) reacting a compound of formula II:

with a compound of formula III:R²—COOH  (III), and a compound of formula IV:R³—NC  (IV), under such conditions that a compound of formula I isformed, wherein R¹ represents a substituted or unsubstituted alkyl,alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, orheterocyclic group, R² represents a substituted or unsubstituted alkyl,alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, orheterocyclic group, and R³ represents a substituted or unsubstitutedalkyl, alkenyl, or alkynyl group, or a reversibly attached protectivegroup.
 2. The process according to claim 1, further comprising: b)isolating a compound of formula I from a reaction mixture.
 3. Theprocess according to claim 2, further comprising: c) subjecting thecompound of formula I obtained in b) to dehydrating conditions to obtaina compound of formula IV:


4. The process according to claim 3, further comprising: reacting thecompound of formula IV with a compound of formula IX or a diastereomerthereof:

and a compound of the general formula X:R⁷—COOH  (X), to obtain a compound of formula XI or a diastereomerthereof:

wherein R⁴ represents each independently, or jointly a substituted orunsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-,di- or tricyclic, or heterocyclic group, R⁵ represents eachindependently a hydrogen atom, a substituted or unsubstituted alkyl,alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, orheterocyclic group, R⁶ represents the structure derived from compound I,wherein the formyl carbon atom is linked to the proline ring, while thehydrogen atom has been removed and wherein R¹, R² and R³ are definedherein above, and R⁷ represents a substituted or unsubstituted alkyl,alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic ornon-aromatic, mono-, di- or tricyclic, or heterocyclic group.
 5. Theprocess according to claim 4, wherein both substituents R⁴ jointly forma substituted or unsubstituted 3-, 4-, 5-, 6-, 7- or 8-membered ringstructure.
 6. The process according to claim 5, wherein R⁴ is chosensuch that the compound of formula I has a structure of formula XII, XIIIor XIV:


7. The process according to claim 4, wherein R⁷ represents a structureof formula XV:

wherein R^(a) and R^(b) each independently represents a hydrogen atom, ahalogen atom, C₁-C₄ alkyl optionally substituted by halogen, acycloalkyl group, an aryl group, a lower alkoxy group, a lower thioalkylgroup, a cycloalkyloxy group, an aralkyloxy group or an alkanoyl group;a hydroxyl group, a nitro group, a formyl group, an amino group whichmay be protected or substituted, a cycloalkyloxy, aralkyloxy, alkanoyl,ureido or mono-, di- or tricyclic heterocyclic group, all of whichgroups may optionally be substituted.
 8. The process according to claim1, wherein R¹ is —CH₂-cyclopropyl or —CH₂-cyclobutyl.
 9. The processaccording to claim 1, wherein R² is acetate.
 10. The process accordingto claim 1, wherein R is cycloalkyl or hydrogen.
 11. The processaccording to claim 1, wherein R¹, R² and R³ are chosen such that thecompound of formula VI has a structure of formula VII:


12. The process according to claim 1, wherein the aldehyde of formula IIhas been derived from a substantially enantiomerically puresubstituted-amino-1-ethanol of formula V:

by A) N-formylation and B) subsequent Dess-Martin oxidation of theN-formylated intermediate.
 13. The process according to claim 12,wherein the Dess-Martin oxidation is carried out in the presence ofR³—NC, so that the acetic acid liberated as a by-product of theDess-Martin oxidation reacts as R²—COOH.
 14. The process according toclaim 1, further comprising: formulating the compound of formula I to apharmaceutical composition.
 15. A compound obtained by the process ofclaim 1.